Genetic defects in the enzymes involved in serotonin metabolism may be implicated in the causation of a wide range of diseases, from eating disorders, obsessional compulsive disorder and alcoholism to autism. Tryptophan, obtained only from the diet in humans, is converted to serotonin by tryptophan hydroxylase, or to kynurenine by tryptophan 2,3- dioxygenase (TDO2). Both enzymes are rate limiting in their respective pathways. The purpose of this study is to screen the TD02 gene for polymorphisms, assess functionality, and search for disease associations in 350 individuals, primarily using single-strand conformational polymorphism (SSCP) analysis. Most of the coding region (11 of the 12 exons) and short regions of the introns was successfully amplified and screened across populations with anorexia or bulemia nervosa, obsessive- compulsive disorder, autism, major depression and suicidality, impulsivity and alcoholism, and subjects enrolled in a tryptophan depletion study. No associations were found for polymorphisms in introns 5 and 6, nor for a mutation in exon 7 (A to C, 749 Asn to His). The promoter region is being screened, no polymorphisms were found in the two TATA boxes, and in the putative glucocorticoid site an A to C variant was detected but with no disease association. However, in the promoter region of GTT repeats, an SSCP variant has been found which, on polyacrylamide gel electrophoresis, manifests both a long and short allele, implying an insertion. This region is currently being sequenced. This variant appears to be associated with impulsivity. A sib-pair analysis of 600 individuals is underway to confirm this finding.